Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Department of Synthetic Medicinal Chemistry, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Mol Med Rep. 2018 Feb;17(2):2373-2383. doi: 10.3892/mmr.2017.8179. Epub 2017 Nov 28.
Activation of kinase-associated signaling pathways is one of the leading causes of various malignant phenotypes in breast tumors. Strategies of drug discovery and development have investigated approaches to target the inhibition of protein kinase signaling. In the current study, the anti‑tumor activities of a novel multi‑kinase inhibitor, T03 were evaluated in breast cancer. T03 inhibited Taxol‑resistant breast cancer cell proliferation and induced cell cycle arrest and apoptosis in vitro and in vivo. The current results demonstrated that T03 downregulated c‑Raf, platelet‑derived growth factor receptor‑β and other kinases, thus inhibited Raf/mitogen‑activated protein kinase kinase/extracellular signal‑regulated kinase and Akt/mechanistic target of rapamycin survival pathways in MCF‑7 and MCF‑7/Taxol xenograft tumors. At a dose of 100 mg/kg, T03 inhibited tumor growth by 62.90 and 59.98% in tumor weight in MX‑1 and MX‑1/T xenograft models, respectively and by 62.60 and 60.22% in MCF‑7 and MCF‑7/T tumors, respectively. These data indicate that the novel multi‑kinase inhibitor, T03, may present as a potential compound to develop novel treatments against breast cancer and Taxol‑resistant breast tumors.
激酶相关信号通路的激活是导致乳腺癌中各种恶性表型的主要原因之一。药物发现和开发的策略已经研究了针对蛋白激酶信号抑制的方法。在本研究中,评估了新型多激酶抑制剂 T03 在乳腺癌中的抗肿瘤活性。T03 抑制紫杉醇耐药乳腺癌细胞的增殖,并在体外和体内诱导细胞周期停滞和细胞凋亡。目前的结果表明,T03 下调 c-Raf、血小板衍生生长因子受体-β 和其他激酶,从而抑制 Raf/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶和 Akt/雷帕霉素机制靶点存活途径在 MCF-7 和 MCF-7/Taxol 异种移植肿瘤中。在 100mg/kg 的剂量下,T03 在 MX-1 和 MX-1/T 异种移植模型中分别抑制肿瘤生长 62.90%和 59.98%,在 MCF-7 和 MCF-7/T 肿瘤中分别抑制肿瘤生长 62.60%和 60.22%。这些数据表明,新型多激酶抑制剂 T03 可能成为开发针对乳腺癌和紫杉醇耐药乳腺癌的新型治疗方法的潜在化合物。